Abstract
Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. Here we report that TBP-like protein (TLP), a member of the TBP family, is a new regulatory factor for the p53-MDM2 interplay and thus for p53 activation. We found that TLP acts to stabilize p53 protein to ensure long-lasting p53 activation, leading to potentiation of p53-induced apoptosis and senescence after genotoxic stress. Mechanistically, TLP interferes with MDM2 binding and ubiquitination of p53. Moreover, single cell imaging analysis shows that TLP depletion accelerates MDM2-mediated nuclear export of p53. We further show that a cervical cancer-derived TLP mutant has less p53 binding ability and lacks a proliferation-repressive function. Our findings uncover a role of TLP as a competitive MDM2 blocker, proposing a novel mechanism by which p53 escapes the p53-MDM2 negative feedback loop to modulate cell fate decisions.
Highlights
Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development
P53 is phosphorylated at Thr-18 and Ser-20, both of which are critical for MDM2 binding, leading to the dissociation of the p53-MDM2 interaction [12, 13]. p300/CBP binds to the p53 transactivation domain (TAD) and acetylates multiple lysine residues in the C-terminal domain of p53 [14], and p53 escapes from degradation and becomes active as a transcription factor [15]
These results suggest that TBP-like protein (TLP) up-regulates p53 at the protein level, which results in inhibition of cell growth through control of p53 target genes
Summary
Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation It remains unclear, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. P53 orchestrates more than 100 target genes, it is usually retained in an “off” state because of its rapid turnover [2] This negative regulation is achieved mainly through recruitment of MDM2 to the transactivation domain (TAD) in the N terminus of p53 and the E3 ubiquitin ligase activity of MDM2 [3,4,5]. In the late phase of the stress response, TBP-associated factor 1 (TAF1), the largest subunit of the basal transcription factor TFIID, phosphorylates p53 at Thr-55 and dissociates p53 from the p21 promoter by elevating MDM2 binding affinity of p53 [17, 18]. Little is known about the most fundamental question of how TLP regulates p53 target genes or p53 itself
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